EGFR is a member of the HER (human epidermal growth factor receptor) glycoprotein family, other members of the family include ErbB2 (HER-2), ErbB3 (HER-3), ErbB4 (HER-4). The intracellular EGFR tyrosine kinase can catalyze the phosphorylation of various substrate proteins, and plays a pivotal role in the signaling pathway of tumor cells. EGFR can activate its intracellular tyrosine kinase under the stimulus of an extracellular signal, transmit the extracellular signal into cells and amplify the signal, thereby regulating the growth and differentiation of cells, angiogenesis and inhibition of apoptosis. Abnormal signaling pathway transmission caused by EGFR over-expression or mutation has a close correlation with the growth, invasion and metastasis of malignant tumors. EGFR expression is progressively increased from normal tissues, pre-cancerous lesions to cancerous tissue, and the EGFR expression level is closely related to the prognosis of cancer patients. Several synthetic drugs can block EGFR-mediated signal transduction, thereby inhibiting the growth of tumor cells and the tumor invasion into surrounding tissue, and promoting the apoptosis of tumor cells. Therefore, EGFR-targeted therapy is one of the current research hot spots. Molecular targeted therapy targeting EGFR has good therapeutic effect in selective population.
Currently, drugs targeting EGFR on the market are mainly divided into two categories: monoclonal antibodies which act on the extracellular domain of EGFR, and small-molecule EGFR tyrosine kinase inhibitors (EGFR-TKI) which act on the binding domain of the intracellular EGFR tyrosine kinase. Moreover, EGFR-TKI drugs are classified into two categories (i.e. reversible and irreversible inhibitors) due to the different binding modes between the drugs and the EGFR tyrosine kinase. Irreversible inhibitors can irreversibly and permanently bind to the protein tyrosine kinase, and continuously reduce the level of the protein tyrosine kinase unless new protein tyrosine kinase is generated. Irreversible inhibitors have longer medicinally effective time. However, FDA application records show that the bioavailability of the existing clinically developed drug Afatinib is merely 11.175%; in the xenograft model using A431 human epidermal carcinoma nude mice, 10 mg/kg dosage of Afatinib shows no pharmacological effect. However, the MTD of Afatinib is 30 mg/kg (see Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene, 2008, 27(34): 4702-4711). Therefore, it is apparent that the therapeutic window of Afatinib is very narrow.